Neuroprotective effects of alpha-iso-cubebene against glutamate-induced damage in the HT22 hippocampal neuronal cell line

作者：Park Sun Young; Jung Won Jung; Kang Jum Soon; Kim Cheol Min; Park Geuntae; Choi Young Whan^*

来源：International Journal of Molecular Medicine, 2015, 35(2): 525-532.

DOI：10.3892/ijmm.2014.2031

• alpha-iso-cubebene
• glutamate
• apoptosis
• cAMP-responsive element binding protein
• Nrf2
• neuroprotection

Since oxidative stress is critically involved in excitotoxic damage, we sought to determine whether the activation of the transcription factors, cAMP-responsive element binding protein (CREB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2, also known as NFE2L2), by alpha-iso-cubebene is involved in its protective effects against glutamate-induced neuronal cell death. Pre-treatment with alpha-iso-cubebene significantly attenuated glutamate-induced cytotoxicity in mouse hippocampus-derived neuronal cells. alpha-iso-cubebene also reduced the glutamate-induced generation of reactive oxygen species and calcium influx, thus preventing apoptotic cell death. alpha-iso-cubebene inhibited glutamate-induced mitochondrial membrane depolarization and, consequently, inhibited the release of the apoptosis-inducing factor from the mitochondria. Immunoblot anlaysis revealed that the phosphorylation of extracellular signal-regulated kinase (ERK) by glutamate was reduced in the presence of alpha-iso-cubebene. alpha-iso-cubebene activated protein kinase A (PKA), CREB and Nrf2, which mediate the expression of the antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1), involved in neuroprotection. In addition, alpha-iso-cubebene induced the expression of antioxidant responsive element and CRE transcriptional activity, thus conferring neuroprotection against glutamate-induced oxidative injury. alpha-iso-cubebene also induced the expression of Nrf2-dependent genes encoding HO-1 and NQO1. Furthermore, the knockdown of CREB and Nrf2 by small interfering RNA attenuated the neuroprotective effects of alpha-iso-cubebene. Taken together, our results indicate that alpha-iso-cubebene protects HT22 cells from glutamate-induced oxidative damage through the activation of Nrf2/HO-1/NQO-1, as well as through the PKA and CREB signaling pathways.

• 出版日期2015-2